Mechanistic insights into HIV-mediated heart failure with preserved ejection fraction

HIV介导的射血分数保留的心力衰竭的机制见解

• 批准号: 9476609
• 负责人: Hossein Ardehali
• 金额: $ 64.68万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9476609
• 关键词: Address; Adverse effects; Age; Aging; Animals; Antioxidants; CCR5 gene; Calcium; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cells; Chronic; Chronic Disease; Comorbidity; Defect; Development; Disease; Drug Targeting; EFRAC; Effectiveness; Exposure to; Failure; Functional disorder; Future; General Population; Genes; Genetic; Genetic Predisposition to Disease; HIV; HIV Infections; Health; Heart failure; Heterogeneity; Human; Immune; Immunologic Deficiency Syndromes; In Vitro; Incidence; Inflammation; Knowledge; Left Ventricular Ejection Fraction; Ligands; Macaca; Macaca mulatta; Measures; Mediating; Mitochondria; Modeling; Muscle Cells; Natriuretic Peptides; Pathogenesis; Pathologic; Pathology; Patients; Persons; Pharmaceutical Preparations; Predisposition; Reactive Oxygen Species; Relaxation; Reporting; Risk; Role; SIV; Soluble Guanylate Cyclase; Stimulus; System; Virus Replication; antiretroviral therapy; cGMP production; cell injury; clinically significant; cytokine; heart cell; improved; in vitro Model; induced pluripotent stem cell; inflammatory milieu; inhibitor/antagonist; insight; microbial; mitochondrial dysfunction; mortality; novel; novel therapeutics; phosphodiesterase V; transcriptome sequencing; treatment strategy

Persons living with HIV (PLWH) now live longer and suffer from many chronic conditions, which occur in PLWH at a higher rate and at an earlier age, and continue to develop despite suppressive antiretroviral therapy (ART). One of the abnormalities commonly found in PLWH is heart failure with preserved ejection fraction (HFpEF), defined as diastolic dysfunction with left ventricular ejection fraction of 50% or more. The development of HFpEF in the general population is associated with an increase in all-cause mortality, highlighting the clinical significance of this disorder. The cellular mechanism of HFpEF in PLWH is not totally understood, but chronic inflammation, genetic predisposition, and side effects of ART have been proposed. In this proposal, we will address the fundamental gap in knowledge of the mechanism of HIV-associated HFpEF using two systems: 1) already established model of isolated cardiomyocytes from rhesus monkey that mimic HFpEF pathology following CCR5 ligand exposure, and 2) human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). We will then simulate chronic inflammation in vitro by treating the cells with cytokines or exposing them to an inflammatory milieu. Our central hypothesis is that mitochondrial pathogenetic mechanisms in cardiomyocytes are triggered by HIV-associated systemic inflammation to cause HFpEF, and that novel therapies can counter the cellular derangements. We also hypothesize that the heterogeneity of susceptibility to HFpEF is due to differences in genetic predilection to these pathologic mechanisms. To study our hypothesis, we propose two aims. In Aim 1, we will determine the pathogenetic mechanisms of HFpEF in cardiomyocytes. Isolated rhesus monkey cardiomyocytes and control hiPSC-CMs from five non-infected, non- HFpEF donors will be exposed to an in vitro model of chronic inflammation using three systems: 1) addition of CCR5 ligands, 2) microbial translocation, and 3) addition of non-CCR5 ligand cytokines, all of which have been demonstrated to be altered in PLWH independent of viral replication. We will then assess the effects of these manipulations on cardiomyocyte relaxation and function by measuring calcium transients, in addition to mitochondrial function and ROS (as markers of cellular injury). We will also treat hiPSC-CMs and isolated cardiomyocytes with ART to rule out a contribution of ART to diastolic dysfunction. Finally, we will generate hiPSC-CMs from 10 HIV patients, 5 with, and 5 without HFpEF and perform RNA-sequencing to identify candidate genes for characterization of the genetic basis of susceptibility to HFpEF. In Aim 2, we will determine whether novel drugs protect cardiomyocytes against the cellular pathogenesis causing HFpEF. We will expose cardiomyocytes from macaque and hiPSC-CMs to an inflammatory environment as described in Aim 1, and will assess whether treatment with drugs downstream of inflammation and ROS (i.e., phosphodiesterase 5/9 inhibitors, soluble guanylate cyclase stimulators, natriuretic peptides, and antioxidants) improve calcium transients and mitochondrial function.

艾滋病毒携带者(PLWH)现在寿命更长，并患有许多慢性疾病，这些疾病发生在PLWH 发病率更高，年龄更早，尽管接受了抑制性抗逆转录病毒治疗(ART)，但仍在继续发展。 PLWH中常见的异常之一是心力衰竭伴保留射血分数(HFpEF)， 定义为左心室射血分数大于或等于50%的舒张期功能障碍。高频脉冲电场的发展 在一般人群中与全因死亡率的增加有关，突出了临床意义 这种混乱的症状。HFpEF在PLWH中的细胞机制尚不完全清楚，但慢性炎症， 基因易感性和抗逆转录病毒治疗的副作用已经被提出。在这项建议中，我们将解决 使用两个系统对HIV相关的HFpEF机制的基本认识差距：1)已经 模拟CCR5后HFpEF病理的恒河猴分离心肌细胞模型的建立 2)人诱导多能干细胞来源的心肌细胞(hiPSC-CMS)。到时候我们会的 通过用细胞因子处理细胞或将它们暴露在炎性介质中，在体外模拟慢性炎症 周围的环境。我们的中心假设是心肌细胞中线粒体的致病机制是 由HIV相关的全身炎症触发，导致HFpEF，而新的治疗方法可以 对抗细胞错乱。我们还假设易感性的异质性 HFpEF是由于对这些病理机制的遗传偏好不同所致。为了研究我们的 假设，我们提出了两个目标。在目标1中，我们将确定HFpEF的发病机制。 心肌细胞。分离恒河猴心肌细胞并对照5例未感染、未感染的恒河猴 HFpEF捐赠者将使用三种系统暴露于慢性炎症的体外模型：1)添加 CCR5配体，2)微生物易位，以及3)非CCR5配体细胞因子的添加，所有这些都已经 在PLWH中被证明是独立于病毒复制的改变。然后我们将评估这些措施的影响 通过测量钙瞬变来控制心肌细胞的松弛和功能 线粒体功能和ROS(作为细胞损伤的标志)。我们还将治疗HiPSC-CMS和分离的 心肌细胞应用ART以排除ART对舒张期功能障碍的贡献。最后，我们将生成 取自10名HIV患者、5名HFpEF患者和5名非HFpEF患者的HiPSC-CMS，并进行RNA测序以鉴定 描述HFpEF易感性遗传基础的候选基因。在目标2中，我们将确定 新药是否保护心肌细胞免受引起HFpEF的细胞发病机制的影响。我们会揭露 心肌细胞从猕猴和HiPSC-CMS转移到Aim 1中描述的炎症环境中，并将 评估炎症和ROS下游药物(即磷酸二酯酶5/9)治疗是否 抑制剂、可溶性鸟苷环化酶激动剂、利钠肽和抗氧化剂)提高钙含量 瞬变和线粒体功能。